The present invention relates to heparanase-like proteins and nucleotides that encode them.
Heparanase is an enzyme that can degrade heparan sulphate as well as heparin proteoglycans (HPG) and heparan sulphate proteoglycans (HSPG). Heparanase activity in mammalian cells is well known. The activity has been identified in various melanoma cells (Nakajima, et al., Cancer Letters 31:277-283, 1986), mammary adenocarcinoma cells (Parish, et al., Int. J. Cancer, 40:511-518, 1987), leukaemic cells (Yahalom, et al., Leukemia Research 12:711-717, 1988), prostate carcinoma cells (Kosir, et al., J. Surg. Res. 67:98-105, 1997), mast cells (Ogren and Lindahl, J. Biol. Chem. 250:2690-2697, 1975), macrophages (Savion, et al., J. Cell. Physiol. 130:85-92, 1987), mononuclear cells (Sewell, et al., Biochem. J. 264:777-783, 1989), neutrophils (Matzner, et al., 51:519-524, 1992, T-cells (Vettel et al., Eur. J. Immunol. 21:2247-2251, 1991), platelets (Haimovitz-Friedman, et al., Blood 78:789-796, 1991), endothelial cells (Godder, et al., J. Cell Physiol. 148:274-280, 1991), and placenta (Klein and von Figura, BBRC 73:569, 1976), and B cells.
Elevated heparanase activity has been documented in mobile, invasive cells, such as metastatic tumour cells. Examples include invasive melanoma (Nakajima et al Science 220:611 (1983)), lymphoma (Vlodavsky et al, Cancer Res. 43: 2704, (1983)), fibrosarcoma (Becker et al, J. Natl. Cancer Inst., 77:417, (1986)), rhabdomyosarcoma (U.S. Pat. No. 4,882,318), mastocytoma, mammary adeno-carcinoma, leukaemia, and rheumatoid fibroblasts. Heparanase activity has also been documented in non-pathologic situations involving the migration of lymphocytes, neutrophils, macrophages, eosinophils and platelets (Vlodavsky et al., Invasion Metastasis 12:112-127, 1992). Heparanase activity is also implicated in inflammation (Hoogewerf J. Biol Chem 270:3268-3277 (1995); WO97/11684), wound healing (Whitelock et al, J. Biol. Chem. 271: 10079-10086, (1996)), angiogenesis (U.S. Pat. No. 5,567,417), inflammatory diseases such as arthritis (including rheumatoid- and osteo-), asthma, lupus erythematosus, allografts, as well as vascular restenosis, atherosclerosis, tumour growth and progression, fibro-proliferative disorders, Alzheimer's Disease (McBubbin et al Biochem. J. 256:775-783 (1999); Snow et al, Neuron 12: 219-234 (1996)) and several others. In general, it may be said that heparanase activity is present in mobile invasive cells in a variety of pathologies. Thus, inhibitors of heparanase are likely to be of great value in the treatment of these.
Further, inhibition of heparan sulphate degradation would inhibit the release of bound growth factors and other biologic response modifiers that would, if released, fuel the growth of adjacent tissues and provide a supportive environment for cell growth (Rapraeger et al., Science 252:1705-1708, 1991).
WO99/11798, WO99/21975, WO99/40207 and WO99/43830 all relate to nucleic acids encoding human heparanase, as well as polypeptides encoded by the nucleic acids.